Open Access Research article

Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

Guillaume Odri123, Pui-Pui Kim12, François Lamoureux12, Céline Charrier12, Séverine Battaglia12, Jérôme Amiaud12, Dominique Heymann12, François Gouin123 and Françoise Redini124*

Author Affiliations

1 INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France

2 Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes, EA3822, Nantes F-44035, France

3 Service d’orthopédie, CHU Hôtel Dieu, Nantes F-44035, France

4 INSERM UMR957, Faculté de Médecine, 1 rue Gaston Veil, 44 035, Nantes Cedex 1, France

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BMC Cancer 2014, 14:169  doi:10.1186/1471-2407-14-169

Published: 10 March 2014

Abstract

Background

Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.

Methods

Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology.

Results

ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases.

Conclusion

These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.

Keywords:
Ewing’s sarcoma; Zoledronic acid; Lung metastases; Animal models